PROJECT SUMMARY/ ABSTRACT Chronic Subdural Hematoma (cSDH) is an extremely common problem, particularly in the aging population, where fluid like collections compress the brain, frequently requiring surgical drainage. After drainage, 25-50% of patients experience post operative neurologic deficits such as weakness or confusion that are often not explained by problems such as seizure, stroke, or mass effect from the fluid and blood. Recent subdural recordings have demonstrated that some of these neurological deficits may be related to waves of spreading depolarization (SD), which cause temporary neurological dysfunction. There is a fundamental gap in knowledge as to how commonly such events are related to neurologic deficits and if they could be targeted with pharmacotherapy to improve outcomes. This knowledge gap represents an important problem because cSDH is expected to be the most common condition treated by neurosurgeons by 2030 and postoperative neurological deficits in elderly patients can have a significant impact on outcomes and secondary risks such as pneumonia and delayed mobilization. Our long-term goal is to develop effective treatments to improve recovery in these patients by targeting SD. The overall objective of this application is to examine the relationship between neurological deficits and SD and to assess feasibility of a pilot trial to determine if a strategy of NMDA-R antagonism can effectively reduce SD and improve clinical recovery. We also plan to study detailed neuropsychiatric outcomes and if these are worse in patients with SD. The central hypothesis is that SD plays a causal role in some neurologic deficits after cSDH drainage. This hypothesis is based on our preliminary data where SD was observed in 15% of such patients. In one case, repeated waves of SD were exactly time locked to development of new language deficit. Guided by this promising preliminary data, we plan to rigorously examine the relationship between SD and neurologic deficits after cSDH drainage in additional subjects (Aim #1). We will then determine feasibility of performing a randomized trial to test if a strategy of NMDA-R antagonism with a brief course of memantine effectively reduces SD and improves neurologic function (Aim #2). Finally, we will determine the time course of neuropsychiatric recovery after cSDH evacuation at day 30, 90, and 180 and assess if this is worse in patients with SD (Aim#3). We expect that these studies will provide exciting new therapeutic approaches for a previously unrecognized pathophysiology in a very common problem. These data will provide the necessary groundwork for larger pivotal trials to test efficacy of such a targeted, physiology based approach.